Process of preparing granulation of medicinal agents



United States Patent PROCESS OF Paul A.

assignors to Tuerclr and Edwin D.

Richardson-Merrell Inc.,

PREPARING GRANULATION 0F MEDHCINAL AGENTS New a corporation of Delaware No Drawing. 7

Filed Claims. (Cl. 167-82) June 28, 1961, Ser. No.

Carkhufl, Cincinnati, Ohio,

York, N.Y.,

This invention relates to a process of preparing granulations of medicinal agents, suitable for high matic tabletting.

The formation compression into preparation of drugs agents cannot be speed, autoof granules of medicinal agents for tablets is for dispensation.

a very important part of the Many medicinal compressed into tablets with high speed tablet-making machinery without previously processing the material to obtain free having binding properties When drugs are not proper the tablet-making dies, a

easily into -fiowing lubricated granules of exacting characteristics. ly prepared they may not feed nd great variations in weight and other physical properties may result. Some such tablets tend handling. Other to break up or dust during subsequent materials simply will not hold together in the shape of a tablet Without the aid of a binder. Some medicinal agents tend to segregate from other the finished tablet.

The natural ten compression into dency satisfactory tablets is components of the tablet, and this results in variations in potency in of some medicinal agents to resist usually overcome by forming granules containing the drug. These granules also contain other cats, dyes and other tabletsubstances such as binding be compressed into good-looking tablets weight and physical properties.

One method of pro-treating tabletting is called components of the t and compressed into slugs which are subseque and screened to the desired slugging.

particle size.

is then treated with a lubricating agent and in this manner to 'An alternative ponents of treated with which is forced through a screen predetermined size.

agents, diluforming aids so that they can of uniform medicinal agents prior to In this operation the dry ablet are thoroughly mixed together ntly ground This material compressed into tablets. Many medicinal agents can be processed obtain granulations suitable for press ing into tablets but others cannot.

the

der and then trays, re-ground and re-screened to obtain granules of a size suitable for c ulation method cannot be use agents.

The slugging t maceutical granules ompression int 0 tablets. The wet grand with some medicinal and wet methods of preparing pharinvolves a number of different steps requiring considerable labor and time and requires various kinds of machinery space. Principal which occupy a objects a process of preparing granulations of drug tive ingredients comprise ulation, suitable for comp which reduces the num labor and time ordin by a [process chinery, the

The objects of very simple manner.

invention, the me excipients are ground to the major portion large amount of of the invention are to provide s, where acof the granression into satisfactory tablets ber of steps, the maarily required.

the present invention are attained in a According to dicinal a fine powder in several types of micropulverizing apparatus,

Abbe impact grinder, a ro minuting machine, ball mills o apparatus which 400 to 80 mesh.

the process of the agent, fillers, binders and other any one of such as an ller mill, a Fitzpatrick com- 1' other micropulverizing will yield particle sizes ranging from The thoroughly blended powders are ice then placed in a conventional coating pan, preferably fitted with bafiles, and adapted to be driven at variable speeds. At the beginning of the process, the pan is rotated at a relatively high speed, about five to thirty revolutions per minute. These pans should be made of stainless steel or some material inert to the medicinal components of the mixture. Water, or an aqueous solution of a binding agent, is then sprayed into the rotating pan in the form of a very fine mist, the particle size of the droplets preferably being uniform and no larger than about 0.2 mm. in diameter. Air guns, such as are used in spraying paint, may be used providing they are fitted with a nozzle and have an air pressure suitable to yield the fine type of spray that is necessary. Spray nozzles which do not require air pressure may also be used. A predetermined amount of Water based on the weight of the dry solids in the pan is added in this manner. This amount will vary depending upon the ingredients comprising the granulation. The speed of rotation should be such that there is a continuous tumbling of material in the pan. About 15-30 revolutions per minute are usually required to produce tumbling in pans having a diameter up to four feet. About 5-15 revolutions per minute will produce satisfactory tumbling in pans having a diameter of six feet due to the increased peripheral speed of the pan. As water is added, granules commence to form. The time required for spraying in the critical amount of water is usually about ten minutes for batches of to 400 kg, although in smaller batches a shorter time is all that is necessary, whereas in larger batches a longer period of time would be required.

When the pulverized powders in the rotating coating pan contain a sufficient amount of water soluble binding agent, the above described process is very effective in developing granules of a suitable size which can be readily dried and pressed into tablets. However, when the therapeutically effective agents comprise a major proportion of the mixture, and particularly where these components are water insoluble or lack adhesive or binding characteristics of their own when wetted and dried, it is necessary to follow particular procedures and observe certain conditions in finishing the granulation. When the amount of the water soluble binding components of the mixture is relatively small because of the necessity for a large proportion of drug in the mixture, the binding action may \be inadequate and a large proportion of fines will tend to develop as a result of the tumbling action of the material in the rotating coating pan, We have discovered, however, that satisfactory granules can be prepared from powdered mixtures in which the therapeutically efiective component comprises the major proportion of the granulation it the tumbling action is discontinued or reduced to a minimum as soon as granules of a desired size are formed and the drying action is completed without excessive agitation of the moist granules.

In accordance with the present invention a fine spray of water, or a granulating solution, is directed onto the tumbling powder mixture in the rotating tablet coating pans as described above until granules of a desired size commence to form. If too much water is added and the tumbling action is continued too long, large balls may result. If insufficient water is applied or if the tumbling action is continued too long, an unduly large proportion of fines results. To avoid the development of large balls of medicament and the development of fines, the spraying and the rapid tumbling action are discontinued as soon as granules of a desired size and moisture content are obtained. It is preferred that the largest proportion of the granules be of such size as to pass through a 12 mesh screen but be retained on a 200 mesh screen.

After suitable granules are formed, the tumbling action is reduced to not more than about three revolutions 3 per minute and may in fact be discontinued completely with intermittent rotation of the pan at the rate of about once every minute. During this time a gentle current of hot air is blown over the tumbling granules. Care should be taken that the current of air be not too strong, 5

otherwise small particles of the material may be blown from the pan. If desired, the pan may be heated from the outside by blowing a stream of hot air on it, or by using a heat-jacketed pan. The tumbling and heating operations are continued until the material in the pan con- To illustrate the invention in greater particularity and 2 demonstrate its advantages over conventionally used methods of preparing granules, a number of granulations were prepared. In one series of experiments the powdered mixture was granulated by the conventional wet granulation method whereas in the terial was invention.

granulated by the processes of the present EXAMPLE I Granulations were prepared with the following formulae: 30

Granulation AF0r A.P.C. Tablets The wet method granules were prepared by granulating the acetophenetidin, caffeine and corn starch in a Day mixer with a solution of ten percent corn starch paste and sixteen percent gelatin. The granulation was passed through a 6 mesh screen while wet, spread on trays and dried overnight at 120 F. They were then dry screened through a 12 mesh screen.

The spray method granules were prepared by placing the powdered ingredients in a tablet coating pan and spraying the powders with a fine spray of water while they tumbled in the pan. When small granules of the material were formed, the speed of the pan was reduced to about one revolution per minute and hot air between the temperatures 400-600 F. was blown over the damp granules until they were dry. After the granules were dried, 4.6 kg. of a commercially available pre-prepared aspirin granulation containing 16 percent starch Was added together with additional starch to bring the total other series, the ma- 25 were mixed by slowly rotating the coating pan after which four percent of corn starch was added as a lubricant.

To the granules prepared by the conventional wet processes there was also added 4.6 kg. of the pre-prepared aspirin granulation, and enough corn starch to bring the total weight up to 8.7 kg. was added as a lubricant. The mix was then dry screened through a 12 mesh screen. Compress on A inch standard punches and dies to form tablets Weighing 518 mg. Similarly, sulfadiazine granulations were prepared with the following formulae:

Granulation BF0r Sulfadiazine Tablets (500 mg.)

Wet Spray method, metho kg. kg.

Sultadiazine 3.0 Corn starch 0. 3 Corn syrup solids 0.075 Soluble starch 0. 15

One batch of the material was granulated in a Day mixer with an aqueous solution containing 5 percent starch paste and 5 percent glucose. The wet mass was then passed through a 6 mesh screen and dried overnight on trays at 120 F. The material was then dry screened through a 12 mesh screen and lubricated with one percent magnesium stearate.

The granules prepared by the spray method were granulated with a fine spray of water, dried as before, lubricated in the pan with one percent of magnesium stearate and screened. Compress on standard inch punches and dies to form tablets weighing 616 mg.

Ascorbic acid granules were also prepared with the following compositions:

Granulatzon "CF0r ASCOIblC ACld Tablets (250 mg.)

Wet Spray method, method, kg. kg.

Ascorbic acid, powdered 1. 605 1.605 Sugar, powdered 0. 54 0. 54

The wet method granules were lating in a Day mixer with 16 percent gelatin solution,

prepared by granuwet screened, dried, screened again and lubricated with one percent magnesium stearate as above.

The wet spray granules were granulated with water as above and dried and lubricated in the pan and screened. Compress on inch standard punches and dies to form tablets weighing 544 mg.

Each of the granules described above was pressed into tablets on a Model RB-2 Stokes single rotary tabletting machine.

The granules and tablets described above were then weight of the granulation to 8.7 kg. These ingredients x mined with the following results.

TABLE I Granulations Tablets Granula- Percent Percent Disintetion Granumoisture Drying moisture Com- Hardness gration General Method lating in wet time in dry pression (Mon- U.S.P. appearsolution, granula- (hours) granulaeharacsanto) method ance ml. tion tion teristics (minutes) Spray H20" 450 9. 4 0.5 2. 19 l 10 0. 1 Wet 1, 600 26. 4 18 1.91 l 8. 5 0.7 2 Spray H" 1, 200 22. 4 0.7 1.8 1 13 15 1 Wet 600 22. 4 l8 1. 4 1 13 13 1 Spray HzO 200 6 0.25 3. 8 1 12 6 1 Wet 225 8. 5 l8 4 2 9 S 2 NOTE. (ev: Compression charaeteristics(l) Good; (2) Capping tendency. General appearance-(l) Good; (2) Spotty, chipping tendency on edges.

To illustrate the saving in time and labor made by practicing the processes of the present invention as contrasted with the conventional wet granulation method,

mesh. These granulations were compressed on a single rotary tabletting machine as were the wet granulation products. The results are shown in the following table:

Norm-Key: Compression characteristics-(l) Good; (2) fair; (3) poor (capping).

Gen-

eral appearance-(1) Excellent; (2) Good; (3) fail g y mottled); (4) Poor (badly mottled and spotted).

the following table illustrates comparative times involved in preparing A.P.C. tablets:

Similar savings are made in the preparation of other granulations.

EXAMPLE II Powdered sugar, phenobarbital and water soluble dye, D and C Green No. 5, were mixed 'at a concentration of 0.5 gram of the dye and 37.5 grams of the phenobarbital per kilogram of powder and micropulverized in a Raymond mill. This color was chosen because it usually causes difficulty in producing smoothly colored tablets when granulated by ordinary methods. 2.5 kilograms of the micropulverized powders were granulated by the conventional wet granulation method. The granulations were made by adding water as the granulating agent to the powder in a small Day mixer. The wet granulations were forced through a six mesh screen and dried overnight on trays in a hot air oven at 120 F. Dried granulations were ground through a twelve mesh screen, lubricated with one percent magnesium stearate and compressed on a Model 'RB-2 Stokes single rotary tabletting machine using inch standard cup punches and dies at a tablet weight of 400 mg.

2.5 kilogram portions of the micropulverized powders were placed in 18 inch stainless steel coating pans having bafiies mounted on the inner periphery. The speed of the pans was controllable from to 30 revolutions per minute by means of a variable speed control mechanism. At the start of the granulation procedure, the pans were rotated at relatively high speed, about 20 to revolutions per minute, and water was sprayed over the tumbling powders from a paint gun for a period of about ten minutes. As the powders were wetted, small granules formed and the speed of the pan was gradually reduced to prevent impaction on the periphery due to centrifugal force. Rotation was continued at such rate that a tumbling of the powders resulted and small round granules were formed. A gentle stream of heated air at a temperature of about 375 F. was blown over the tumbling granules and the speed was further reduced to about three revolutions per minute. The dry granulated material was lubricated with one percent of magnesium stearate and then screened to the desired size, about 12 Similarly, granulations were prepared using various binding agents including such mixtures a: powdered sugar, corn starch, 10%; lactose, 90%, corn starch, 10%; mannitol, 98%, powdered gelatin, 2%; mannitol, 88%, powdered gelatin, 2, corn starch, 10%; powdered sugar, 50%, lactose, 25%, corn starch, 25%; powdered sugar, 90%, corn syrup solids, 10%. In each case, the granules had better compression characteristics and the tablets had a better general appearance than did those prepared from similar powdered mixtures which were granulated by the conventional wet granulation method.

400 milligram tablets were prepared from granulations made by the process of the present invention in which thiamine hydrochloride (10 mg. per tablet) or ascorbic acid (50 mg. per tablet) were incorporated in the micropulverized powders. In each case the same superior results and savings in labor and processing time were obtained.

The process of the present invention also has a number of other important advantages. For instance, it is particularly adapted to the preparation of granules containing moisture sensitive therapeutic agents. The conventional wet granulation process uses a considerable amount of moisture in preparing the granules and requires a protracted drying time to remove the moisture from the granules to condition them for compressing on conventional tabletting machinery. Moisture sensitive therapeutic agents often suffer from this treatment. In contrast thereto, the low amount of moisture applied to the material by the process of the present invention during formation of the granules and the rapid drying time reduce losses due to degradation of moisture sensitive materials.

Even though the stream of air used to dry the tumbling granules may be as high as 500 F., the high rate of evaporation of the moisture or other granulating liquid from the granules and the tumbling action during the drying process, maintains the temperature within the granulation within safe limits Also the time of exposure of the sensitive material to moisture is greatly reduced.

The granulations of the present invention may be colored by micropulverizing pigments, lakes or dyes along with the other tablet ingredients before they are introduced into the pan. Alternatively, water soluble dyes may be distributed on the material in the tumbling pan as the granulations are being formed. Also, solutions of dyes in volatile solvents such as alcohol or chloroform, may be added to the powdered material either prior to granulation or during the granulation process.

The granules may be lubricated with conventional lubricating agents such as magnesium stearate or other stearate, starch, talc or the like, by simply mixing these materials with the formed granules in the rotating pan. This avoids a step which is commonly performed as a separate step in the wet granulation procedure. The application of a final spray of 0.25 percent to 0.5 percent of a light mineral oil to the granules tends to eliminate further dusting and provides a gloss to the tablet.

This application is a continuation-in-part of applica- 7 tion Serial No. 17,490, filed March 15, 1960, and now abandoned, and of application Serial No. 17,491, filed March 25, 1960, and now abandoned.

We claim: 1. In a method of preparing granulations suitable for compressing into tablets on automatic high speed pharof 0.4 to 8 percent by weight by contacting the surface of the slowly tumbling granules with a stream of heated dry air.

2. In a method of preparing granulations suitable for compressing into tablets on automatic high speed pharslowly tumbling granules with a stream of heated dry air.

3. In a method of compressing into tablets on automatic high speed pharmaceutical tabletting machines the improvement which of preparing a micro-pulverized mixmixed powders in a tablet coating pan and rotating the pan at speeds within the range 5 to 30 revolutions per minute, whereby the powdered mixture is caused to tumble, spraying the surface of the tumbling powders with a fine spray of water, the particles of said spray being less than 0.2 mm. in diameter, until granules are formed by adhesion of the tumbling solid particles, and when the granules have developed to a particle size Within the range 200 to 12 mesh reducing the rate of rotation of the coating pan to 1 to 5 revolutions per minute and drying the moist granules to a moisture content of 0.4 to 8 percent by Weight by contacting the surface of the slowly tumbling granules with a stream of heated dry air.

5. In a method of preparing granulations suitable for compressing into tablets on automatic high speed pharmaceutical tabletting machines the improvement which comprises the steps of preparing a micro-pulverized mixture of a small amount of a medicinal agent and at least 60 percent by weight of sucrose, the said mixture having particle sizes within the range 400 to mesh, placing the mixed powders in a tablet coating pan and rotating the pan at speeds within the range 5 to 30 revolutions per minute, whereby the powdered mixture is caused to tumble, spraying the surface of the tumbling powders with a fine spray of water, the particles of said spray being less than 0.2 mm. in diameter, until granules are formed by adhesion of the tumbling solid particles, and when the granules have developed to a particle size within the range 200 to 12 mesh reducing the rate of rotation of the coating pan to 1 to 5 revolutions per minute and drying the moist granules to a moisture content of 0.4 to 8 percent by weight by contacting the surface of the slowly tumbling granules with a stream of heated dry air.

6. In a method of preparing granulations suitable for compressing tablets in automatic high speed pharmaceutical tabletting machines the improvement which comprises the steps of tumbling a finely divided mixture of solids having a particle size within the range of 400 to 80 mesh said mixture containing a medicament in a tablet coating pan rotating at speeds within the range 5-30 revolutions per minute, spraying the surface of said tumbling powders with a fine spray having a particle size not in excess of 0.2 mm. of an aqueous solution containing a non-toxic, orally acceptable, water soluble binding agent whereby the fine particles of solids are caused to adhere and form granules of a size within the range the tumbling granules until the granules are dried.

7. In a method of preparing granulations suitable for compressing into tablets on automatic, high speed, pharmaceutical tabletting machines the improvement which comprises preparing a micro-pulverized mixture having a particle size within the range 400 to 80 mesh of at least 60 percent by weight of a one to 40 percent by weight of a non-toxic, orally acceptable, water soluble binding agent, placing the mixed powders in a tablet coating pan and rotating the pan at speeds within the range 5 to 30 revolutions per minute, .sufiicient to cause the powdered mixture to tumble, subjecting the surface of the tumbling powders to a fine spray of water, the particle size of which is less than 0.2 mm. in diameter, until granules having an average particle size of less than 12 mesh but greater than 200 mesh are formed, reducing the rate of rotation of the coating pan and the tumbling action in the pan to an extent that the surface of the granulation is renewed only about once in one minute, and blowing air at 400 F. to 600 F. on the granules, whereby the granules are dried to a moisture 9 content suitable for compression, discontinuing the rotation of the pan before substantial disintegration of the granules occurs, and thereafter passing the granules through a 12 mesh screen to obtain free flowing granules suitable for tabletting on automatic machinery.

References Cited in the file of this patent UNITED STATES PATENTS Peebles Sept. 9, 1958 Lachrnan et a1. Cavanaugh Sienkiewicz et a1 Mar. 10, 1959 Dec. 1, 1959 Mar. 28, 1961 

1. IN A METHOD OF PREPARING GRANULATIONS SUITABLE FOR COMPRESSING INTO TABLETS ON AUTOMATIC HIGH SPEED PHARMACEUTICAL TABLETTING MACHINES THE IMPROVEMENT WHICH COMPRISES THE STEPS OF PREPARING A MICROPULVERIZED MIXTURE OF A MEDICAL AGENT AND A SOLID, NON-TOXIC, ORALLY ACCEPTABLE, BINDING AGENT, THE SAID MIXTURE HAVING PARTICLE SIZES WITHIN RANGE 400 TO 80 MESH, PLACING THE MIXED POWDERS IN A TABLE COATING PAN AND ROTATING THE PAN AT SPEEDS WITHIN THE RANGE 5 TO 30 REVOLUTIONS PER MINUTE, WHEREBY THE POWDERED MIXTURE IS CAUSED TO TUMBLE, SPRAYING SURFACE OF THE TUMBLING POWDERS WITH A FINE SPRAY OF SOLVENT FOR SAID BINDING AGENT, THE PARTICLES OF SAID SPRAY BEING LESS THAN 0.2 MM. IN DIAMETER, UNTIL GRANULES ARE FORMED BY ADHESION OF THE TUMBLING SOLID PARTICLES, AND WHEN THE GRANULES HAVE DE VELOPED TO A PARTICLE SIZE WITHIN THE RANGE 200 TO 12 MESH VEDUCING THE RATE OF ROTATION OF THE COATING PAN TO 1 TO 5 REVOLUTIONS PER MINUTE AND DRYING THE GRANULES TO A MOISTURE CONTENT OF 0.4 TO 8 PERCENT BY WEIGHT BY CONTACTING THE SURFACE OF THE SLOWLY TUMBLING GRANULES WITH A STREAM OF HEATED DRY AIR. 